摘要:

Gene therapy approaches pursuing immunological strategies for the treatment of malignant melanoma play major roles in the current efforts to explore the potential benefits of gene transfer technologies for medicine. This may be explained by the nearly complete resistance of advanced metastatic melanoma towards conventional non-surgical treatment modalities, and the particular immunogenicity of melanoma in connection with a presumed immunogene therapeutic ‘field effect’. The latter relates to the potency of the immune system to amplify gene transfer effects that are limited due to the imperfection of the currently available gene delivery systems. The ongoing clinical trials focus predominantly on treatment safety and tolerability rather than efficacy. The corresponding tumor-immunological background is reviewed, focusing on a treatment concept centred on tumor-reactive, cytotoxic CD8+ T effector ce

ISSN:1660-5527    

DOI:10.1159/000211469

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The European Community directive, imposing that effects claimed for cosmetic actives must be validated using non-animal procedures, has stimulated the use of in vitro models for pharmacotoxicological trials. In this paper, an efficacy study of a new biopeptide, a hydrolysate obtained by fermentation of milk proteins, was performed using an in vitro skin equivalent (SE). This SE is obtained by seeding normal human kera-tinocytes onto a dermal equivalent comprising a collagen-gly-cosaminoglycan(GAG)-chitosan porous matrix populated by normal human fibroblasts, which neosynthesize their own extracellular matrix (ECM). A gel containing 2% milk biopeptide was applied topically (10 μl) every 2 days during 15 days. Subsequent investigations of the biopeptide effects were based on morphological criteria after histological analysis and on synthesis of ECM components. Collagen and GAG synthesis were measured by tritiated proline, glucosamine and Na235SO4 incorporation. Qualitatively, the histological features of the biopeptide-treated SEs showed a thicker epidermis than the untreated control SEs, where only a few layers of stratum corneum were observed. The dermal porous matrix seems to be more filled by neosynthesized ECM than the control. Quantitatively, milk biopeptide treatment induced a significant activation of hyaluronic acid (+46%) and sulfated GAG (+53%) synthesis, whereas only non-significant increases of total protein and collagen synthesis were observed (Student’s test, p < 0.00

ISSN:1660-5527    

DOI:10.1159/000211470

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We have used a series of bisindolylmaleimide selective pro-tein-kinase C (PKC) inhibitors to investigate the role of this enzyme in the regulation of cell proliferation in mouse hair follicle organ cultures. Mouse whisker follicles were isolated by microdissection, and rates of DNA synthesis during culture were determined from 3H-thymidine incorporation. The bis-indolylmaleimides Ro 31-7549, Ro 31-8161, Ro 31-8425 and Ro 31-8830 inhibit isolated brain PKC with IC50 values of 8-80 nM, 60-fold less potent against protein kinase A, and inhibit PKC-mediated protein phosphorylation in platelets with IC50 values in the range 0.25-4.4 μM. These PKC inhibitors were found to increase levels of mouse hair follicle DNA synthesis, with EC50 values in the range 1-4 μM and maximal levels in the range 151-197% of control. Ro 31-7549 had an IC50 value 50-fold lower than that of minoxidil, while the maximal level of DNA synthesis for the PKC inhibitor was 86% higher. Incubation of mouse hair follicles with Ro 31-7549 resulted in a delay of approximately 24 h in the onset of decline in follicular DNA synthesis rates. Ro 31-6045 and Ro 31-7208, bisindolylmaleimides without activity in the platelet PKC assay, did not affect mouse hair follicle DNA synthesis rates. Taken together, these findings show that PKC mediates, at least in part, the rapid loss of proliferative activity that occurs in mouse whisker follicles in culture, and provide further evidence that PKC plays a role as a negative proliferative signal in hair follicle

ISSN:1660-5527    

DOI:10.1159/000211471

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Cyclosporm A (CyA), a fungal metabolite with potent immuno-suppressive activity and an antiproliferative effect on epithelial cells, i.e. normal and transformed keratinocytes, is currently proposed in the treatment of psoriasis, where its use is limited mainly by possible nephrotoxicity and/or hepatotoxicity. Numerous analogs of CyA have been produced and studied. The most promising of these is the immunosuppressive analog cyclosporin G (CyG), in which norvaline is substituted for alpha-aminobutyric acid at the 2 position. This would maintain strong immunological activity, with reduced to absent nephro-toxic and hepatotoxic effects. The authors compared the antiproliferative effect of CyG and CyA on the epidermoid carcinoma cell line A431 in vitro, performing the MTT-microculture tetrazolium colorimetric assay based on the ability of viable cells to reduce the MTT compound to a blue formazan product. Subconfluent A431 cells were incubated with CyA or CyG or solvent only, for 24, 48, 72 or 96 h at concentrations of in vivo relevance (0.3, 0.6, 1.25, 2.5, 5, 7.5, 10 μg/ml). CyA and CyG showed similar antiproliferative effects, in low-serum-containing media in a dose- and time-dependent manner. After 24 h of incubation, the inhibition of the growth rate was irrelevant. A striking inhibition of the growth rate at the higher concentrations of the drugs (7.5 and 10 μg/ml) at 72 and 96 h of incubation was evident. Therefore CyG has been demonstrated to exercise an antiproliferative effect on the A431 cell line. These data suggest possible use for CyG in the treatment of immune-mediated disease, particularly in the treatment of dermatologic diseases characterized by epidermal hyperplasia and/or kerati-nocyte hyperproliferatio

ISSN:1660-5527    

DOI:10.1159/000211472

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The functional consequences of using topical retinol on skin have not been thoroughly studied so far. The aim of this open study was to compare two preparations containing either retinol or vitamin E, using biometric evaluations. Three methods, namely the sodium lauryl sulfate (SLS) corneosurfametry bioassay, the ultraviolet (UV) squamometry test and optical profilometry of the UV-induced wrinkling process, were used to assess some properties of the stratum corneum. The retinol preparation achieved better scores than the vitamin-E cream in all three tests and appears to improve the resistance of the stratum corneum against some chemical (SLS) and physical (UV) threats. It also limits UV-induced shallow wrinkling.

ISSN:1660-5527    

DOI:10.1159/000211473

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Tamol is widely used in the therapy of inflammatory derma-toses. It has pronounced astringent properties and is able to inactivate the neutrophil-derived elastase. Since plasminogen activation and release of mast cell chymase may occur in acute dermatitis, we investigated the inhibitory properties of tamol for these enzymes. Tamol proved to be a potent inhibitor of plasmin and mast cell chymase in concentrations relevant for use in dermatotherapy. The inhibition of mast cell chymase and plasmin by tamol was linear and non-competitive. The inactivation of proteolytic enzymes with the capacity to degrade extracellular-matrix proteins may be one of the major clinical effects of tamol in the treatment of acute inflammatory dermatoses.

ISSN:1660-5527    

DOI:10.1159/000211474

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Chronic exposure to a weak irritant leads to inflammatory changes which may be followed by pigmentary changes and accommodation. The inflammatory responses to acute exposure to an irritant have been extensively studied. This study investigated quantitatively the inflammatory reactions produced in photodamaged skin with chronic application of a weak chemical irritant (tretinoin cream 0.025%) over a period of 9 months (36 weeks). Forty-eight subjects with moderately to severely photodamaged skin were enrolled in a 36-week, double-blind placebo-controlled study. Tretinoin cream was applied nightly on the distal two thirds of one dorsal forearm and placebo on the other. The proximal third of each dorsal forearm received no treatment and served as control. Clinical assessments and diffuse reflectance measurements were made at 7 time points during treatment. Apparent concentrations of oxyhemoglobin (HbO2), deoxyhemoglo-bin (Hb) and melanin were estimated by analysis of the diffuse reflectance spectra. No changes were observed in the apparent H bO2or the Hb concentration of the placebo-treated or control sites, thus establishing a reliable baseline. The apparent HbO2 concentration of the tretinoin-treated sites increased significantly from baseline to a maximum at 12-18 weeks of treatment, then returned to baseline with continued applications. The changes in HbO2 concentration agreed closely with clinical assessments of erythema. The apparent melanin concentration, corresponding to diffuse hyperpigmentation, showed a large seasonal decrease in both the control and the treated sites, with an additional decrease in the treated sites between 12 and 18 weeks. Erythema appeared after repeated applications and eventually resolved under continuous treatment. The maximum decrease in hyperpigmentation occurred simultaneously with the maximum increase in erythema.

ISSN:1660-5527    

DOI:10.1159/000211475

出版商:S. Karger AG    

年代:1997

数据来源: Karger